Acerta® Disposable Filling System

The Evolution of a New Disposable Filling Technology for Sterile Pharmaceuticals

Presented May 4, 2004

By Jim Furey, Product ManagerMillipore Corporation

Innovative Enabling Technologies for Disposable Manufacturing

Presentation Outline

Introduction

Background on Technology

Prototype Systems

Current Hardware Design

Scale-up of Technology

Disposable Component

Validation / Qualification

Introduction

Technology is scheduled to be launched in middle of 3rd

Quarter of this year (not yet commercially available)This technology with disposable and pre-sterile product contacts parts was pursued as part of our Disposable Manufacturing InitiativeInitiative includes expanding our product line offerings beyond our filtration product lines (Opticap® and Millipak®) to include product more complete process unit operationsDesigned to give the marketplace options to help speed the time to clinic & market and/or reduce the capital investment required for initial product development along with enhanced process securityThe initiative also has resulted in our recent BioprocessingAlliance with Hyclone which gives us access to their Bioprocess Container product line with the CX5-14 Film

Why Adopt Disposable Manufacturing Technologies?Enhanced Process Security

PDA-Identified Major Sources of Contamination*

1. Personnel contamination2. Non-routine activity3. Aseptic assembly4. Human error5. Mechanical failure6. Airborne contaminants7. Improper sanitization8. Surface contaminants9. Material transfers 10. Failure of 0.2 µm filter11. Failure of HEPA12. Improper sterilization

* PDA Industry Aseptic Processing Survey 2001

Minimize Process RiskEliminates cleaning after use Reduced CIP or SIPMinimizes validation effortsComplete containment of product Increase cleanliness, reducing risks for operators

Background on Technology

Short History

The patents covering the technology “Volumetric Fluid Dispensing Apparatus” by Denis Keyes et. al. were licensed by Millipore

Before licensure there were a few iterations of the technology produced

We took the last iteration, made some improvements in design and performance and designed a system for demonstration and testing with the assistance of a consulting engineer with a background in filling machine technology

The effort lead to Millipore’s first prototype system

Technology HighlightsIt enhances product and operator safety

Does not require autoclaving or steam-in-place

Eliminates aseptic assembly of parts

Offers the total containment of product

Disposable component eliminates the need for post-use cleaning

Disposable assembly easily snaps to hardware component

Multiple head flexibility

Designed for new or existing filling lines

Patented gravimetric / volumetric dispensing system based mainlyusing the interaction of optical sensors and pinch valves

Intended for use with final sterile injectables- initial filling capability for small volume, aqueous liquids (approx. 0.2 to 10 grams)

Animation of Filling Process with the Acerta System

Prototype System

Prototype System Operation-Interation of Light Sensors and Pinch Valves

Light Sensor-Detects Liquid to Activate Cycle Change

Volume Adjusted-by Changing Upper Sensor Position

Data From Trial of Acerta Prototype System

Trials completed in November 2002 at Pharmacia (now Pfizer) in Nerviano, ItalyComplete Presentation first delivered by Per Sivertsson from Pfizer at the PDA Conference in Prague- February 2003Presentation Title “Disposable systems an interesting alternative for aseptic manufacturing”Excerpts now presented courtesy of Pfizer

Pharmacia-PDA presentation modified for PDA Chapter meeting- Acerta Only.ppt

Outcome of Market Analysis (Including Testing at Pfizer)

Design improvements to make it more sanitary for an aseptic processing area

Optimized for wipe downRemoval of fan for cooling the control panel

Improvement in setting the initial target fill weight

Easier to use operator interface for production personnel

Functionality to prevent product loss and downtime

Have a version to be used for small scale productionDesigned for low hold-up volumeDesigned for optional use in a Biological Safety Cabinet for Manual Filling (small foot print)Scalable to a Four Head (or multi-head) system

Current Hardware Design-Modular Design

Single Head - Designed for Integration to Filling Line or used in a BSC (to be avail.)

Four Head - Designed for Integration to Filling Line (only beta version now)

Acerta™ Hardware ComponentsFilling Line Integration

Main Components (excluding enclosure):

• Power Supply (not shown)• Integrated Circuit Board (ICB)• Capacitance sensor for product reservoir level

control system• Pinch Valves• “Towers” consisting of:

• Servo positioning motor w/control board• Light sensors• Slide mechanism to move the top sensor

• Handheld Computer (with preprogrammed firmware)

Logic

Program communicates

via RS485 Motor control board to drive motor to position top light sensor

Handheld interface

ICBPinch Valves for filling

Light sensors

Controls valves and light sensors depending upon position of 5-postion knob

Alarm logicICB

Capacitance sensorICB

Manual Filling Specific Qualification-Microbiological Challenge Successful

Test Completed in Biological Safety Cabinet - SG603 from The Baker CompanyProduct Protection Test -Challenged with a bacterial aerosol spore concentration of 8 X 10^6 spores per ml delivered each 5 minutes (as per NSF).Personnel Protection-Challenged with a bacterial aerosol spore concentration of 8 X 10^8 spores per ml delivered each 5 minutes (as per NSF)Tests run in triplicateResults - Pass

Acerta System in Action

Single Head System

Four Head System

..\Video\2004 Videos\Single head on a filling line\Acea.mpg

..\Video\2004 Videos\AcertaTS.rm

Three Modes of Operation

Manual Dispense Button

Foot Switch

Signal From a Filling Line

I/O ConnectionsConnector Signal

J1Computer

RS485

J2Pump

Peristaltic Feed Pump Control

J3Inputs

Dispense Signal From Filling Line

Signal from Filling Line if Vial is Missing

J4Outputs

Fill complete signal

External Alarm Signal

J5Footswitch

Foot switch input

Scale-up of Technology to Multi-head Systems

Partner with Filling Machine Manufacturers (OEM Program)

Have discussed the technology with the major companies in the industryAt an end-users request, they are willing and able to integrate the system to their filling lineMarket Survey was conducted on their expectations from Millipore to support the OEM ProgramThey liked the modular design

We want to stick to our core competence in the area of in the delivery of process solutions in the area of the disposable assemblies (where the OEMs have little expertise and experience)

Scale-up of Technology Options

Sterifill F 200 , photo courtesy of www.ima.it

Portable System (shown previously)

Integrated System (here)

Acerta Disposable Assembly

Single Head

• Removes the need for validated cleaning procedures and increases safety

• All liquid contact parts are completely disposable

Four HeadBeta Assembly

• Arrives triple-bagged and sterile (by gamma)

Acerta Disposable Assembly Highlights

Materials

Reservoir — LDPE product contact layer

Tubing — Platinum cured Silicone and Pharmed

Fittings — HDPE

Needles — Polycarbonate

All materials not toxic per USP Class VI Biological Test for Plastics

Pre- Sterilized - Gamma Radiation using validated methodology

Tripled bagged and boxed and tested per ISTA 2A

LAL Bacterial Endotoxins Test ≤ 0.5 Eu/mLMeet TOC Specifications for WFI (<0.5 ppm TOC)

100% Integrity Tested using a validated leak test

Must maintain integrity after being pressurized at 1 psi for 8 hours

Meet USP 26-NF21 sec 788 for particles

Acerta Hardware Highlights

Filling Performance0.2 – 1g @ 40 fpm

≤ 5g @ 20 fpm

≤ 10g @ 10 fpm

≤ 20g @ 7 fpm (0.5 – 1g at +/- 5mg; > 1g at +/- 0.5%)

CE Compliant

IP 54 Enclosure rating

Easy access to pinch valves for maintenance

Validation, Qualification, and Implementation of Acerta System Into Your Process

Application Support: “Will it work with my products attributes?”Handled by local Applications Specialist with support from R&D Applications Engineering via demo systems

Will have available cost model

Extractables from Disposable AssemblyWill offer Extractables Validation Support Program similar to filter extractables program via our state-of-the-art Accesssm Service LabsComponents were optimized in R&D ProgramProtocol developed System Acceptance Testing

Support customers in product adsorption protocol development

Disposable Assembly Certificate of Quality with Lot Release Criteria (Including lot sterilization information)

Hardware Developed Using GAMP Life Cycle Methodology GAMP 4 V-model

Hardware Validation Documentation Package Only

Hardware Execution services

USER REQUREMENT SPECIFICATION related to

related to

related to

FUNCTIONAL SPECIFICATION

DESIGN SPECIFICATION

PERFORMANCE QUALIFICATION

SYSTEM

BUILD

OPERATIONAL QUALIFICATION

INSTALLATION QUALIFICATION

Source: GAMP Supplier Guide

Class 1000

LAF Class 100

PassThrough

Class 10 000

Future Disposable Final Fill and Finish Clean Room Process

Pump

Holding bag2

holding

bagdilution

bag

Peristaltic pump

WFI prep. bag

dilution Bag

Summary of Potential Benefits

Advantages of:•No CIP

•No SIP

•No Aseptic Assembly of Parts

Offers potential benefits of:

•Reduced set-up time

•Improved turnaround time

•Reduced validation efforts

•Reduced risk of contamination

•Speed in time to market

AcknowledgmentsMillipore R&D Team

Ernie Jenness

Brett Belongia

Naren Renganath

Mike Scanlan

Mike Pearce

Michael Joens

Steve Hunt

Millipore Videographer

Dan Arrington

Millipore MarketingJean-Marc CappiaNeil HolmanGiuseppe PaganiniMark McInnesMaurice Phelan

Consultant / InventorDenis Keyes

Pfizer

Per Sivertsson

Angelo Columbo

Others who gave feedback